Molecular Mechanisms Associated with Insomnia and Response to Cognitive Behavioral Therapy for Insomnia

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Sleep disturbances highly prevalent conditions, especially following traumatic brain injury (TBI); ~60% of patients with TBI have insomnia. Chronic sleep disturbances impair daily functioning, negatively impact quality of life, are linked to impaired cognition and alertness, and contribute to depression, anxiety, and PTSD symptoms— common comorbidities in veterans with TBI. The “gold standard” for insomnia treatment is Cognitive Behavioral Treatment for Insomnia (CBTi). However, ~40% of individuals with insomnia do not respond to CBTi. In this study, we will capitalize on an on-going DoD-funded cohort of 160 active-duty personnel with insomnia to test the overarching hypothesis that among patients with insomnia, those with TBI vs. no-TBI will manifest higher levels of systemic inflammation and inferior responses to CBTi. Participants will be divided into 4 groups: Group A (no insomnia, no TBI), Group B (Insomnia only, no TBI), Group C-low (Insomnia + low grade TBI), and Group C-high (Insomnia + high grade TBI). Participants will age, sex match across all groups and further match with age-related chronic conditions, and medication history. All participants completed a baseline blood collection and clinical assessment. Participants diagnosed with insomnia completed a 60-minute CBTi sessions over 6 weeks and returned 12 weeks after baseline enrollment for blood collection and clinical evaluation. Peripheral blood samples will be sequenced (RNA-seq) at baseline and after CBTi for evaluation of gene expression profiling and bioinformatics analysis. We will test the following hypothesis: Aim 1 will test the hypothesis that insomnia severity and the corresponding baseline (pre-CBTi) peripheral blood inflammatory status displays a hierarchy: Groups C-high > C-low > B > A. Aim 2 will test the hypothesis that the CBTi-associated reductions in insomnia severity will display a hierarchy (best to worst): group B > C-low > C-high; correspondingly, the associated reduction in inflammatory status will be most, intermediate, and least in these groups, respectively. Using well-established bioinformatic approaches in the nominee’s mentor’s laboratory, genes that are differentially expressed between study groups will be identified, and mechanistic pathways associated with the proposed hierarchy will be determined. We will utilize a recently developed a strategy to categorize gene signatures into those that relate to immunocompetence vs. inflammation. With this framework, we anticipate that expression levels signifying the conjoined high immunocompetence-low inflammation state will be overrepresented in controls/no-insomnia group vs. those with insomnia. We anticipate that the hallmark of the insomnia/high grade TBI group to be characterized by low immunocompetence-high inflammation. Improving sleep is the first step in optimizing rehabilitation strategies and the proposed study will provide novel insights to help improve sleep in Veterans with and without risk of previous TBIs. These insights may have long-term implications to the health and well-being of veterans, including identification of potential biomarkers (gene expression) to assist in prognostication and monitoring treatment. The proposed study will also have a relatively equal representation of men and women, which can further help inform gender-specific care in the military and Veteran health care system and for the development of military and Veteran health policy. The long-term beneficiaries from this study will be individuals with insomnia in the chronic phase of recovery from TBI. The research proposed coupled with expertise of the mentors, provides the nominee with an unparalleled opportunity to expand critical skillsets necessary to develop a pragmatic, translational ‘omics’-based sleep medicine program within the VA system that is broadly applicable to many diseases beyond insomnia.